1. Field of the Invention
The present invention relates to the field of organ transplantation. In particular, the present invention provides transgenic swines and swine cells having human HLA-D genes, which provides organs or tissues for xenotransplantation.
2. Description of the Prior Art
Due to the shortage of human organs or tissues for transplantation, it is desired to seek xenogenic sources. Recently, xenotransplantation of pig organs into humans is a promising strategy for the reason that pigs provide the organs or tissues of a suitable size for xenotransplantation into humans. However, the use of pigs as an organ source is limited because transplantation of a pig graft-organ into a human results in various rejections of the graft-organ including hyperacute, acute and chronic rejections. Recently transgenic pigs were generated to down regulate the pathway of complement activation causing hyperacute rejection, such as the transgenic pigs introduced with a gene encoding human decay accelerating factor (hDAF), see Cozzi et al. (1994) Transplant Proc., 26, 1402-1403; and McCurry et al. (1995) Nat. Med, 1, 423-427; with a gene encoding membrane cofactor protein (MCP), see McCurry et al. (1995); and with a gene encoding CD59, see McCurry et al. (1995); and Fodor et al. (1994), Proc. Natl. Acad. Sci. USA, 91:11153-11157. However, the xenograft of transgenic pig organ into a primate would be rejected due to cell-mediated rejections, including not only hyperacute rejection, but also acute and chronic rejections. All of the rejections must be taken into consideration, in the use of pig organs for xenotransplantation.
The class I molecules of Human leukocyte antigen (HLA-I) were used to generate transgenic pigs for use as an organ source to provide graft-organs without a reduced human nature killer (NK) cell rejection. For instance, Seebach et al. (2000), see U.S. Pat. No. 6,030,833, provided a genetically engineered swine cell having a transgene encoding a human HLA A, HLA B, HLA C or HLA G transgene, wherein expression of the transgene minimizes human nature killer (NK) cell rejection Saaki et al. (1999), Transplantation, 67, 31-37 also disclosed a HLA-G transgenic pig wherein HLA-G expression protects porcine endothelial cells against NK cell-mediated xenogenic cytoxicity.
It is found that HLA-DP typing concordance in allotransplantation is more important than HLA-I matching. HLA-DQ and HLA-DP transgenic mice were generated and studied, such as Tsuji et al. (1993), Transplant Proc., 25, 136-137, Hagihara et al. (1994), Transplant Proc., 26, 967-968; Hagihara et al. (1994), Transplant Proc., 26, 1868; Hagihara et al. (1996), Transpl. Immunol., 4, 220-226; and Tsuji et al. (1994), Transplant Proc., 26, 2441-2443. However, it is not considered that mice are a suitable organ source due to the small sizes of their organs.
Furthermore, Tu et al. (1999), Int. Surg., 84. 176-182, provided two lines of HLA-DP tansgenic pigs to study the role of HLA-DP in xenotransplantation, wherein the integration of the transgene had been confirmed by PCR, DNA sequencing, and Southern blot analysis; and the expression of the transgene had also been proved by RT-PCR. In the HLA-DP transgenic pigs, the expression of HLA-DP antigen on peripheral blood mononuclear cells was reduced, see Tu et al. (1998), Transplant Proc., 30, 3502-35031. The expression of xenogenes were detected in organs or tissues of HLA-DP transgenic pigs, see Lee et al. (2000). Transplant Proc., 32:7; and Lee et al. (1999), a presentation at the 6th Congress of the Asian Society of Transplantation, Singapore, P.310 (Abstract). The function of HLA-DP on xenotransplantation was confirmed by primed mix lymphocyte culture with HLA-DP transgenic pigs"" peripheral blood mononuclear transgenic pig cells see Tu et al. (1998), Transplant Proc., 30, 3502-35031.
It is still desired to seek more humanized and suitable organ sources for xenotransplantation into humans.
One object of the invention is to provide a transgenic swine, which has a human HLA-DQ or HLA-DR transgene, wherein expression of said transgene reduces a xenogenic cellular response between pig and human.
Another object of the invention is to provide an isolated swine cell, which has a human HLA-DQ or HLA-DR transgene, wherein expression of said transgene reduces a xenogenic cellular response between pig and human.
Another further object of the invention is to provide a graft, in particular a graft-organ of a graft-tissue, which is derived from the transgenic swine of the invention.